Aging is a phenomena in which the functions, applicability and resistance of an organism reduces over time. With the globally aging at an accelerating pace, delaying the negative aspects of aging is vital for advancing the human life span and quality of life. The aging of multiple organs can lead to a lot of disease and no exception for cardiovascular system. Actually, one of the primary risk factors for cardiovascular diseases is aging because of altered cardiovascular metabolism resulting in metabolic disorders and inflammation. In this review, we discuss about the relationship of oxidative stress with aging and FoxO proteins, which is essential factor for anti-aging of cardiovascular systems.

1. Research Article
Oxidative Stress & FoxO Transcription
Factors on Cardiovascular Aging -
Juewon Kim1,2*
and Siyoung Cho1
a
Beauty Food Research Institute, R&D Center, AmorePacific Corporation, Yongin-si, Gyeonggi-do
446-729, Republic of Korea
b
Department of Integrated Biosciences, University of Tokyo, Chiba 277-8562, Japan
*Address for Correspondence: Juewon Kim, R&D center, Amorepacific, Yongin-si, Gyeonggi-do
446-729, Korea. Tel: +82 31 280 5964; Fax: +82 31 281 8392;Email: jwkim@amorepacific.com (J.Kim);
csy1010@amorepacific.com (S. Cho)
Submitted: 19 November 2015; Approved: 28 December 2015; Published: 03 January 2016
Citation this article: Kim J, Cho S. Oxidative stress & FoxO transcription factors on Cardiovascular
aging. Int J Cardiovasc Dis Diagn. 2016;1(1): 001-004.
Copyright: © 2016 Kim J, et al. This is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
International Journal of
Cardiovascular Diseases & Diagnosis

2. SRL Cardiovascular Diseases & Diagnosis
SCIRES Literature - Volume 1 Issue 1 - www.scireslit.com Page - 002
Keywords: Aging, Cardiovascular, FoxO transcription
factor, oxidative stress, reactive oxygen species
Aging is a phenomena in which the functions, applicability and
resistance of an organism reduces over time. With the globally aging
at an accelerating pace, delaying the negative aspects of aging is vital
for advancing the human life span and quality of life. The aging of
multiple organs can lead to a lot of disease and no exception for
cardiovascular system. Actually, one of the primary risk factors for
cardiovascular diseases is aging because of altered cardiovascular
metabolism resulting in metabolic disorders and inflammation. In
this review, we discuss about the relationship of oxidative stress with
aging and FoxO proteins, which is essential factor for anti-aging of
cardiovascular systems.
Oxidative stress and Aging
The free radical/oxidative stress theory of aging first proposed
by Harman (1953) suggested that the accumulation of irreversible
molecular damage caused by reactive oxygen species (ROS) is
one of the most significant factors in aging [1]. It is believed that
irreversibly oxidised biomolecules do not function properly and that
the accumulation of oxidised biomolecules accelerates aging. This
theory has been supported by a number of studies in various model
organisms demonstrating a correlation between aging and redox state
or demonstrating an increase in longevity associated with exogenous
treatment with various antioxidants [2-4]. Therefore, understanding
the aging-related alterations induced by changes in redox state will
provide a clue to anti-aging strategies that may be applied in complex
organisms.
Oxidative stress and FoxO
transcription factors
It has been reported that moderate oxidative stresses promote
the nuclear localization of FoxO, resulting in the expression of
target genes [5]. This process results in both lifespan extension and
metabolic changes in aging model organism nematode, C. elegans [6].
The relatively recent development of this more nuanced view presents
a challenge to the biomedical research community in terms of the
possible assessment of the significance of ROS and scavenging of
ROS in biological systems [5]. As many researches have shown [7-8],
FoxO plays a pivotal role in redox signaling, but it is unclear whether
and how redox signaling to and from FoxO contributes to its effects
on longevity. One emerging theme is that the consequences of FoxO
activation depend on the cellular environment and can produce a
switch in the FoxO-mediated gene expression profile. FoxO protein
expression, subcellular localization, and transcriptional activity
are regulated predominantly by two modes of signaling, namely,
antioxidant-induced PDK-1/SGK-1 signaling and oxidative stress-
induced JNK-1/MST-1 signaling. FoxO localization is regulated
differently by the PDK-1/SGK-1 and JNK-1/MST-1 signaling
pathways [5, 9]. In addition to this mechanism, a number of other
post-translational modifications control the activity of FoxO. Most
likely, the physiological response triggered by FoxO is determined
by cellular context as well as the cofactors involved, although the
mode of action through which cell context modifies FoxO is yet to
be fully determined. ROS are known to regulate FoxO transcriptional
activity through posttranscriptional modifications including
phosphorylation, which changes the ability of FoxO to transactivate
target-gene transcription. The effects of ROS on FoxO activity depend
on cellular context, duration, and possibly the intensity of ROS
accumulation.
An effective redox strategy for
anti-aging by regulate cellular
redox state
FoxO activation can induce cell cycle arrest through the direct
induction of multiple changes in factors associated with the cell
cycle transition [10]. The cell cycle arrest induced by FoxO can
influence the eventual outcome in terms of cell fate and may also
promote DNA damage repair and stress resistance. In our previous
results [5], antioxidants appear to act as inducers of DNA repair. The
transcription levels of the cell cycle arrest- and DNA repair-related
genes were increased, but the transcription levels were decreased
in antioxidant-treated cells. Under low/moderate oxidative stress
conditions, GADD45 has been shown to be a downstream target of
FoxO that mediates DNA repair mechanisms and regulates growth
arrest at the G2-M checkpoint. Although oxidant treatment did not
affect these cell cycle arrest and DNA repair genes at our experimental
concentrations, higher concentrations of oxidants increased the
expression of these genes significantly. However, the oxidant
concentrations required to increase these genes are much higher than
the optimal concentration for FoxO nuclear translocation. FoxO
proteins also play a significant role in regulating whole-body energy
metabolism [11]. FoxO activation results in the repression of a large
number of nuclear-encoded genes with mitochondrial functions, a
process mediated by the FoxO-dependent inhibition of c-Myc. The
expression of the metabolism-related genes decreased under the
antioxidantcondition.Inaddition,theexpressionofthemitochondrial
gene decreased under antioxidant conditions. Antioxidant-mediated
FoxO activation may regulate mitochondrial activity through the
inhibition of c-Myc function. Moreover, the expression levels of
these genes were increased at oxidant concentrations higher than
our experimental concentration but decreased under severe oxidative
stress.
Our previous data suggest that antioxidants work as protectors,
maintaining cell integrity by DNA repair [5]. Antioxidants may also
exert calorie restriction-like effects by inhibiting the insulin pathway,
one of the major signaling pathways in calorie restriction-induced
longevity, possibly through c-Myc inhibition. Therefore, antioxidants
appear to act primarily by helping active cells maintain cell integrity
and attenuate any unnecessary hyperactivity. In contrast, oxidant
treatment can activate detoxification enzymes that are typically
reduced in aged cells, which could promote aged cell recovery and
revitalisation by inducing detoxification and energy hormesis. These
different mechanisms of action suggest that there may be a way to
maximise the positive effects of antioxidants and oxidants to achieve
lifespanextension.However,inhigheranimals,suchasmiceorhumans,
there may be much more variation in the optimal concentration of
FoxO nuclear translocation due to individual genetic backgrounds,
the physiological conditions of specific organs and tissues, and
specific cell types. The key might be in the fine tuning of FoxO activity
in response to certain ROS levels and cellular environments, leading
to the most appropriate cell fate decision (detoxify, arrest and repair
or initiate apoptosis or senescence) for whole-organism longevity like
as propose for proteostasis or mitohormesis. A personalised approach
may yield good results in humans if applied after thorough genetic,
physiological, and biochemical analyses of a patient’s organs, tissues,
and cells accompanied by the development of a local delivery system
that can deliver an antioxidant or an oxidant where they are needed.

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The critical role of FoxO in
cardiovascular function
FoxO stimulates cell growth and proliferation and also
decreases VEGF secretion and mediates eNOS phosphorylation,
vasorelaxation and angiogenesis by Akt kinase [12]. The action
of Akt on its downstream target FoxO determines a function in
cardiocascular physiology [13]. The alteration of FoxO signaling
plays an important role in many cardiovascular pathological
processes such as atherosclerosis, cardiac hypertrophy, and vascular
remodeling. FoxO induces pro-apoptotic Bcl-2 family of proteins or
stimulates expression of death receptor ligands such as Fas ligand
and tumor necrosis factor-related apoptosis-inducing ligand, TRAIL.
It can also enhance the levels of cyclin dependent kinase inhibitors.
Phosphorylation of FoxO by Akt inhibits the transcriptional functions
of FoxO and leads to decrease Bcl-2 and increased cell survival [14].
Furthermore, endothelial cell-directed deletion of FoxO1 in adult
mice induced overzealous proliferation along with reduced apoptosis
[15]. However, in endothelial cells, FoxO1 inhibits transcription of
endothelial nitric oxide synthase (eNOS) and accelerates inducible
NOS expression in response to oxidative stress, leading to generation
of peroxynitrite and endothelial dysfunction [16] which contributes
to atherogenesis. In addition, ablation of the three genes encoding
isoforms of FoxO in endothelial cells blocks atherosclerosis in low-
density lipoprotein receptor knockout mice [17]. Fine-tuning of
FoxO is essential to controlling cellular functions in cardiovascular
function.
Atherosclerosis
In atherosclerosis, lability and abolish of the plaque leads to
myocardial infarction, which could be caused by apoptosis of vascular
smooth muscle cells [18]. FoxO seems to have an action in smooth
muscle cell apoptosis through insulin/insulin-like growth factor 1
(IGF1) receptor signaling. Reduced IGF1R signaling and inhibition
of phosphorylation of Akt, FoxO3a and GSK3 induce apoptosis of
vascularsmoothmusclecells[19].InhibitionofAktinvascularsmooth
muscle cells can result in significant increase in phosphorylation of
JNK and c-jun, pro-apoptotic proteins, opposite manner in immune
cells [20]. In addition, FoxO1 regulates asymmetric dimethyl-
arginine through downregulation of dimethyl-aminohydrolase 1 in
endothelial cells and subjects with atherosclerosis [21]. These studies
strongly suggest that FoxO is a pivotal element in the regulation of
endothelial activation.
Vascular remodeling
Vascular remodeling process is composed of changes of
cell growth, death, migration and generation or degradation
of extracellular matrix [22]. FoxO proteins act a pivotal role in
pathogenesis of vascular remodeling. Akt substrate GSK3β has an
essential role in smooth muscle proliferation [23]. Recent study also
reveals that growth arrest-specific protein 6 delays senescence in
vascular smooth muscle cells through the FoxO signaling pathway
[24]. In restenosis and atherosclerosis, increased proliferation of
vascular smooth muscle cells contribute to medial thickening. FoxO
also affects the activity of adventitia in the vasculature. In case of
arterial injury, FoxO activity is remarkably lower in the adventitia and
attributes the increased proliferation of adventitial fibroblasts [25].
Cardiac hypertrophy
Cardiac hypertrophy can be defined at a cellular level as elevated
cardiomyocyte cell volume [26]. In normal growth, physical condition
and growth induced by pathologic stimulation are the major types of
cardiac hypertrophy [27]. Maladaptive hypertrophy could be caused
as a response to excessive hemodynamic workload or by genetic
mutations. Over-expression of Akt induces cardiac hypertrophy,
which may lead to heart failure. Preventing cardiac hypertrophy
by inhibiting mTOR failed to prevent the decline in mitochondrial
function, but glucose utilization was maintained [28]. Reducing
FoxO-mediated transcriptional activation of mitochondrion-targeted
nuclear genes results in repressed expression of mitochondrial
regulation. In myocytes, Akt activation abolished mitochondrial
bioenergetics, which could be partially reversed by maintaining
nuclear FoxO [29]. Constitutively activated Akt could raise the
angiogenesis in heart and contribute to adaptive cardiac hypertrophy.
Later stage of this can lead to heart failure [30]. There is a dilemma
cause exercise is known to increase the cardiovascular health by
raised Akt activity [31]. There must be a fine balance among with the
optimal and maladaptive FoxO activation levels and duration which
is yet to be investigated.
Summary and Perspectives
Aging is a phenomenon in which the functions, adaptability and
resistance of an organism decrease over time, which are triggered by
mainly accumulated oxidative stress. The aging of multiple organs
can ultimately lead to diseases and the cardiovascular system is no
exception. In fact, aging is primary risk factors for cardiovascular
diseases by altered cardiovascular metabolism, metabolic disorders
of the extracellular matrix, abnormal apoptosis, and inflammation.
Therefore, delaying many of the negative aspect of cardiovascular
aging is vitally important for improving the human healthy life span
and quality of life. Most of the studies on FOXO on cancer research,
there are some similarities between pathological conditions in
cardiovascular diseases and the hallmarks of cancer. Although, more
studies should be done to understand actions of ROS and FOXO in
cardiovascular diseases, there is a mandatory need to develop potent
tissue specific inhibitors or activators of the FOXO pathway for
cardiovascular research and therapeutic interests.
Acknowledgments
The authors are grateful to the Caenorhabditis Genetics Center
for the C. elegans strains.
Author Contributions
The author(s) have made the following declarations regarding
their contributions. JK and SC wrote and discussed the paper.
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